Despite the rapid growth in our knowledge of mitochondrial DNA sequence variation, our understanding of its evolutionary significance remains unsatisfying. With the exception of some mitochondrial mutants in lower eukaryotes (such as petite and drug resistant yeast and poky Neurospora), the data mostly serve as a description of the geographic pattern of variation of unknown consequence. In higher eukaryotes, cytoplasmic male sterility and leaf variegation are examples of the few phenotypic traits showing stable cytoplasmic transmission. Is the ubiquity of mitochondrial DNA variation reflected in a general but subtle variation in cytoplasmically inherited fitness characters? The aim of the proposed study is to gain an understanding of the joint evolution of the joint evolution of nuclear genetic and cytoplasmic variation. This will be accomplished by first formally stating a theoretical model for the population genetics of a nuclear gene segregating two alleles in a population that is polymorphic for two cytoplasmic types. Analysis of various extensions of the model, allowing different components of selection, mutation and migration will yield conditions for the maintenance of nuclear and cytoplasmic variation. Strains of Drosophila melanogaster of diverse geographic origin will be screened for cytoplasmic effects and nuclear-cytoplasmic inter-action in viability and fecundity. An elaboration of the classical reciprocal backross design will be performed, using substitution backcrossing to test the stability of transmission of cytoplasmic factors. Strains from a local population will likewise be tested in an effort to quantify within-population variation. The disruptive effects of hybrid dysgenesis will be avoided by performing all experiments with P-cytotype flies. Ultimately these studies will provide a theoretical foundation for understanding nuclear-cytoplasmic interaction, and we will begin quantify the extent to which variation in fitness is inherited cytoplasmically.